Project Summary The lifetime prevalence of voice disorders in the adult United States population is 30% with point prevalence rates of 6.6% to 7.5%. These disorders are debilitating and can lead to significant socioemotional consequences, loss of income, and long-term disability. Point prevalence and census estimates suggest that nearly 20-23 million adults may experience dysphonia annually, with the cost of treatment and lost wages approaching $13 billion dollars. These annual direct costs are comparable to those associated with chronic obstructive pulmonary disease, asthma, diabetes, and allergic rhinitis. Among otolaryngology evaluations for dysphonia, nearly 43% of short-term disability claims are associated with phonotraumatic lesions. Thus, improving the care of patients with voice disorders remains a significant public health need. As a necessary and essential first step to address this need, our research program has established a systematic effort in discovery and pre-clinical testing in the area of voice disorders. Our efforts to date have provided critical new insights into the cellular and molecular pathophysiology of phonotrauma and novel approaches that can support studies of gene/protein, structure, and function in pre-clinical models. In this five-year proposal, we concentrate our efforts on the safety and efficacy of treatments for acute phonotrauma. We focus on a class of steroid hormones extensively used in humans, despite a limited understanding of mechanisms and indications for use, safety, and demonstration of efficacy. Beyond the anti-inflammatory actions, emerging evidence supports a role for glucocorticoids in the maintenance of the epithelial barrier. As a result, glucocorticoids have evolved as a first line therapy for many inflammatory diseases and disorders involving impaired epithelial barrier function. Unfortunately, despite widespread clinical use, the specific effects of glucocorticoids on the vocal fold epithelial barrier remain unknown. The need for treatment efficacy research in voice disorders has been acknowledged as a high priority area in the NIDCD strategic plan. The development of phase I/II/III clinical testing in humans strongly depends on pre-clinical studies to provide information regarding mechanisms underlying therapeutic safety and efficacy. Federal regulations require demonstration of safety and efficacy prior to the approval of large-scale human trials. Pre-clinical testing is thus necessary not only to improve care, but also to reduce the burden of voice impairment on patients and society. To address this need, our research program is well-positioned to launch a systematic effort on the efficacy of treatments for voicedisorders. In the current proposal, we will test the pharmacodynamics of glucocorticoids using in vitro and in vivo preclinical models in order to determine the mechanism of action, desired activity, and drug safety profile of glucocorticoids.